A cohort of 711 multiple sclerosis patients has been identified who had onset of their disease between 1960 and 1969 and resided in either King or Pierce Counties, Washington or in Los Angeles Countu, California in 1970. By 1980, 252 of these patients had progressed to a non-ambulatory status (malignant course), 160 were walking only with the use of aids (intermediate course), and 299 were still ambulatory (benign course). Studies of this cohort have suggested that multiple sclerosis patients changed their place of residence more frequently in childhood than unaffected controls and that a malignant course of disease is associated with older age at onset, being male and residing in Los Angeles County. We now propose one study on the risk of acquiring multiple sclerosis and two studies of factors affecting the course of already acquired multiple sclerosis. The three studies proposed are 1) continued follow-up of a cohort of patients with onset between 1960-69 to confirm that age at onset, sex, place of residence after onset and symptom complex occurring in the first year can predict the subsequent course of disease, 2) a case-control study to determine if frequency of changes of residence in early life, the age at which these occurred and the latitudes within which or between which they occurred infuence the risk of acquiring disease and 3) an immunogenetic study to determine whether genetic and/or immunologic markers are associated with the course of disease. These studies will provide information about the environmental factors and the biologic mechanisms involved in the natural history of MS and should help differentiate early in the disease course those patients who will have a benign or malignant course of disease. This information should be helpful in counseling patiets and their families and in designing efficient clinical trials of therapeutic agents.